Glucagon, a hormone released from pancreatic α cells, plays a key role in maintaining euglycemia. New insights into the signaling pathways that control glucagon secretion may stimulate the development of novel therapeutic agents. In this study, we investigated the potential regulation of α cell function by G proteins of the G _q family. The use of a chemogenetic strategy allowed us to selectively activate G _q signaling in mouse α cells in vitro and in vivo. Acute stimulation of α cell G _q signaling led to elevated plasma glucagon levels, accompanied by increased insulin release and improved glucose tolerance. Moreover, chronic activation of this pathway greatly improved glucose tolerance in obese mice. We also identified an endogenous G _q -coupled receptor (vasopressin 1b receptor; V1bR) that was enriched in mouse and human α cells. Agonist-induced activation of the V1bR strongly stimulated glucagon release in a G _q -dependent fashion. In vivo studies indicated that V1bR-mediated glucagon release played a key role in the counterregulatory hyperglucagonemia under hypoglycemic and glucopenic conditions. These data indicate that α cell G _q signaling represents an important regulator of glucagon secretion, resulting in multiple beneficial metabolic effects. Thus, drugs that target α cell–enriched G _q -coupled receptors may prove useful to restore euglycemia in various pathophysiological conditions.

Glucagon, a hormone released from pancreatic α-cells, is critical for maintaining euglycemia and plays a key role in the pathophysiology of diabetes. To stimulate the development of new classes of therapeutic agents targeting glucagon release, key α-cell signaling pathways that regulate glucagon secretion need to be identified. Here, we focused on the potential importance of α-cell G_s signaling on modulating α-cell function. Studies with α-cell-specific mouse models showed that activation of α-cell G_s signaling causes a marked increase in glucagon secretion. We also found that intra-islet adenosine plays an unexpected autocrine/paracrine role in promoting glucagon release via activation of α−cell G_s-coupled A_2A adenosine receptors. Studies with α-cell-specific Gα_s knockout mice showed that α-cell G_s also plays an essential role in stimulating the activity of the Gcg gene, thus ensuring proper islet glucagon content. Our data suggest that α-cell enriched G_s-coupled receptors represent potential targets for modulating α-cell function for therapeutic purposes.

Following a meal, glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), the 2 major incretins promoting insulin release, are secreted from specialized enteroendocrine cells (L and K cells, respectively). Although GIP is the dominant incretin in humans, the detailed molecular mechanisms governing its release remain to be explored. GIP secretion is regulated by the activity of G protein–coupled receptors (GPCRs) expressed by K cells. GPCRs couple to 1 or more specific classes of heterotrimeric G proteins. In the present study, we focused on the potential metabolic roles of K cell G _s . First, we generated a mouse model that allowed us to selectively stimulate K cell G _s signaling. Second, we generated a mouse strain harboring an inactivating mutation of Gnas , the gene encoding the α-subunit of G _s , selectively in K cells. Metabolic phenotyping studies showed that acute or chronic stimulation of K cell G _s signaling greatly improved impaired glucose homeostasis in obese mice and in a mouse model of type 2 diabetes, due to enhanced GIP secretion. In contrast, K cell–specific Gnas -KO mice displayed markedly reduced plasma GIP levels. These data strongly suggest that strategies aimed at enhancing K cell G _s signaling may prove useful for the treatment of diabetes and related metabolic diseases.

Selenium is an essential micronutrient with a wide range of biological effects in mammals. The inorganic form of selenium, selenite, is supplemented to relieve individuals with selenium deficiency and to alleviate associated symptoms. Additionally, physiological and supranutritional selenite have shown selectively higher affinity and toxicity towards cancer cells, highlighting their potential to serve as chemotherapeutic agents or adjuvants. At varying doses, selenite extensively regulates cellular signaling and modulates many cellular processes. In this study, we report the identification of Delta–Notch signaling as a previously uncharacterized selenite inhibited target. Our transcriptomic results in selenite treated primary mouse hepatocytes revealed that the transcription of Notch1, Notch2, Hes1, Maml1, Furin and c-Myc were all decreased following selenite treatment. We further showed that selenite can inhibit Notch1 expression in cultured MCF7 breast adenocarcinoma cells and HEPG2 liver carcinoma cells. In mice acutely treated with 2.5 mg/kg selenite via intraperitoneal injection, we found that Notch1 expression was drastically lowered in liver and kidney tissues by 90% and 70%, respectively. Combined, these results support selenite as a novel inhibitor of Notch signaling, and a plausible mechanism of inhibition has been proposed. This discovery highlights the potential value of selenite applied in a pathological context where Notch is a key drug target in diseases such as cancer, fibrosis, and neurodegenerative disorders.

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that promotes postprandial insulin release and euglycemia. Although GIP is the dominant incretin in humans, the precise mechanisms regulating GIP release from enteroendocrine K cells in vivo remain to be elucidated. Heterotrimeric G proteins of the G _i family regulate numerous key physiological functions. To explore the potential role of these proteins in modulating K cell function in vivo, we analyzed mutant mice that allowed us to selectively stimulate G _i signaling in K cells or studied mice lacking functional G _i in K cells only. Stimulation of K cell G _i signaling in vivo and in vitro led to reduced GIP release via an exchange protein directly activated by 3ʹ-5ʹ-cyclic adenosine monophosphate 2–dependent pathway and various metabolic deficits. In contrast, inactivation of this class of G proteins in K cells caused elevated plasma GIP levels and pronounced improvements in glucose homeostasis in lean and obese mice. These data provide important insights into the mechanisms of GIP release.